Alaseem Ali M
Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
Saudi Pharm J. 2023 Oct;31(10):101790. doi: 10.1016/j.jsps.2023.101790. Epub 2023 Sep 16.
Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study.
癌细胞的生长和存活通常依赖多种途径，这导致了治疗抗性以及治疗效果的有限性。联合疗法已成为一种有利的方法，可提高治疗效果，并将获得性抗性和有害副作用降至最低。小鼠双微体2（MDM2）蛋白通过负调控肿瘤抑制蛋白p53来调节细胞增殖并促进癌症相关活动。在多种人类癌症中均报道了MDM2异常，这使其成为癌症治疗的一个有吸引力的靶点。因此，已经开发了几种小分子MDM2抑制剂，目前正在临床研究中进行调查。然而，已表明单独抑制MDM2不足以实现对肿瘤生长的长期抑制，从而促使需要进一步研究联合治疗策略。在本综述中，对可能的临床和临床前MDM2联合抑制剂方案进行了全面分析和讨论。考虑到正在评估MDM2抑制剂联合应用的临床试验，它为在癌症管理中将MDM2抑制剂与其他治疗方法联合提供了理论依据。该综述探讨了MDM2抑制剂与化疗或靶向治疗联合应用的现状，以及MDM2抑制剂与免疫治疗联合应用的有前景的方法。此外，它还研究了PROTACs作为MDM2降解剂在癌症治疗中的作用。对这些联合方案的全面审查突出了推进MDM2抑制剂治疗和改善癌症患者临床结局的潜力，并为这一有前景的研究领域的未来研发奠定了基础。
